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Molecular Pharmacology

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Research ArticleArticle

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Woon Chien Teng, Jing Wen Oh, Lee Sun New, Michelle D. Wahlin, Sidney D. Nelson, Han Kiat Ho and Eric Chun Yong Chan
Molecular Pharmacology October 2010, 78 (4) 693-703; DOI: https://doi.org/10.1124/mol.110.065839
Woon Chien Teng
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Jing Wen Oh
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Lee Sun New
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Michelle D. Wahlin
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Sidney D. Nelson
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Han Kiat Ho
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Eric Chun Yong Chan
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Abstract

Fatalities stemming from hepatotoxicity associated with the clinical use of lapatinib (Tykerb), an oral dual tyrosine kinase inhibitor (ErbB-1 and ErbB-2) used in the treatment of metastatic breast cancer, have been reported. We investigated the inhibition of CYP3A4 by lapatinib as a possible cause of its idiosyncratic toxicity. Inhibition of CYP3A4 was time-, concentration-, and NADPH-dependent, with kinact = 0.0202 min−1 and Ki = 1.709 μM. The partition ratio was approximately 50.9. Addition of GSH did not affect the rate of inactivation. Testosterone protected CYP3A4 from inactivation by lapatinib. The characteristic Soret peak associated with a metabolite-intermediate complex was not observed for lapatinib during spectral difference scanning. However, reduced carbon monoxide (CO)-difference spectroscopy did reveal a 43% loss of the spectrally detectable CYP3A4-CO complex in the presence of lapatinib. Incubation of either lapatinib or its dealkylated metabolite with human liver microsomes in the presence of GSH resulted in the formation of a reactive metabolite (RM)-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In addition, coincubation of lapatinib with ketoconazole inhibited the formation of the RM-GSH adduct. In conclusion, we demonstrated for the first time that lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National University of Singapore (NUS) [Grants R-148-000-100-112, R-279-000-249-646, R-148-000-117-133]; the NUS Department of Pharmacy [Final Year Project Grant R-148-000-003-001]; and the Biomedical Research Council, Agency for Science, Technology, and Research.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065839.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    MBI
    mechanism-based inactivator
    RM
    reactive metabolite
    ACN
    acetonitrile
    HLM
    human liver microsome
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    Ki
    inactivator concentration at half-maximum rate of inactivation
    kinact
    inactivation rate constant at infinite inactivator concentration
    Kobs
    observed inactivation rate constant
    DMSO
    dimethyl sulfoxide
    ESI
    electrospray ionization
    EP
    entrance potential
    CE
    collision energy
    CXP
    collision cell exit potential
    QTOFMS
    quadrupole, orthogonal acceleration time-of-flight tandem mass spectrometer
    IDR
    idiosyncratic drug reaction
    MIC
    metabolite-intermediate complex
    LAPA
    lapatinib
    i-FIT
    the likelihood that the isotopic pattern of the elemental composition matches a cluster of peaks in the spectrum.

  • Received April 25, 2010.
  • Accepted July 6, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Woon Chien Teng, Jing Wen Oh, Lee Sun New, Michelle D. Wahlin, Sidney D. Nelson, Han Kiat Ho and Eric Chun Yong Chan
Molecular Pharmacology October 1, 2010, 78 (4) 693-703; DOI: https://doi.org/10.1124/mol.110.065839

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Research ArticleArticle

Mechanism-Based Inactivation of Cytochrome P450 3A4 by Lapatinib

Woon Chien Teng, Jing Wen Oh, Lee Sun New, Michelle D. Wahlin, Sidney D. Nelson, Han Kiat Ho and Eric Chun Yong Chan
Molecular Pharmacology October 1, 2010, 78 (4) 693-703; DOI: https://doi.org/10.1124/mol.110.065839
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